1. Field of the Invention
The present invention relates to novel glycyrrhetinic acid derivatives which can be used as the main active components of medicaments for the treatment of virus infections.
2. Description of the Prior Art
Glycyrrhetinic acid and certain of its derivatives are known to have anti-ulcer, anti-inflammatory, antiallergic, anti-hepatitis and antiviral activity. Among such compounds known so far in the art, for instance, there are carbenoxolone (U.S. Pat. No. 3,070,623), glycyrrhetinic acid ester derivatives having substituents at the 30-position (U.S. Pat. No. 3,070,624), amino acid salts of glycyrrhetinic acid (Japanese Patent Publication No. 44-32798), amide derivatives of glycyrrhetinic acid (Belgian Patent No. 753773), amide derivatives of 11-deoxoglycyrrhetinic acid (British Patent No. 1346871), cicloxolone ("Journal of Antimicrobial Chemotherapy", Vol 18, Suppl. B, pp. 185-200 (1986)), and glycyrrhizic acid and its derivatives ("Chem. Pharm. Bull.", 39(1), pp. 112-115 (1991)). Apart from these, we have also come up with a novel method of synthesizing 11-deoxoglycyrrhetinic acid (Japanese Patent Laid-Open Publication No. 59-70638) as well as its hemi-ester derivatives (Japanese Patent Laid-Open Publication No. 58-8044) and its carboxylic acid and amide derivatives (Japanese Patent Laid-Open Publication No. 63-135351).
As already noted, glycyrrhetinic acid and its derivatives have a variety of useful pharmacological activities. Never until now, however, has there been any report that they have sufficient antiviral for therapeutic use. In addition, they have some serious drawbacks, e.g., they show cytotoxicity in tests where they are used at concentrations high enough to achieve antiviral activity, they are unstable in aqueous solutions, and so on.
In recent years, other antiviral agents, based on acyclovir, based on a nucleic acid have been developed and found to be clinically efficacious against herpes virus infections in particular. However, another problem has arisen in connection with resistant viruses (e.g., thymidine kinase negative one) infections ("Oral. Surg. Oral. Med. Oral. Pathol", Vol. 67, pp. 427-432 (1989)). These nucleic acid type antiviral drugs have also generally been known to be ineffective against RNA virses such as influenza virus. In addition, it has been pointed out that they have some therapeutic effects in pill or injection forms, but they are no or little effective when applied to the site of infection as an ointment ("Antiviral Research", Vol. 14, pp. 305-321 (1990)).
Among antiviral agents other than the nucleic acid type antiviral agents and agents effective against DNA viruses, for instance, phosphonoformate (PFA for short; see "Nippon Rinsho", Vol. 47 (2), pp. 390-394 (1989)), phosphonoacetate (PAA for short; see "Nippon Rinsho", Vol. 47 (2), pp. 390-394 (1989)) and cicloxolone ("Journal of Antimicrobial Chemotherapy", Vol. 18, Suppl. B. pp. 185-200 (1986)) have been known. However, problems with phosphonoformate and phosphonoacetate are that they have side effects such as renal disorders and anemia, whereas cicloxolone has not an antiviral activity high enough for therapy.
Groups of antiviral agents other than the nucleic acid type antiviral agents and agents effective against RNA viruses, for instance, amantadine ("Shonika Sinryo", Vol. 54(4), pp. 988-994 (1991)), remantadine ("Shonika Sinryo", Vol. 54(4), pp. 988-994 (1991)) and LY253963 (a thiadiazol derivative; "Shonika Sinryo", Vol. 54(4), pp. 988-994 (1991)) have been known. Amantadine and remantadine have been shown to be efficacious against influenza A virus but not against influenza B virus, and pose a grave problem--a side effect on the central nerve. LY253963 has been shown to be resistant to influenza viruses in animal tests, but its clinical efficacy has yet to be verified.
Recent knowledge of the gene structure of hepatitis C virus (HCV) that is a leading cause of post-transfusion hepatitis has indicated that it is a single stranded RNA virus having a full length of about 9.5 kilobases ("Science", Vol 244, pp. 359-362 (1989)). However, because HCV is a virus very likely to mutate and is not well understood how it replicates, the development of vaccines or anti-HCV drugs is still very slow ("Shindan To Tiryo", Vol. 80(2), pp. 295-302 (1992)).
For instance, AZT and DDI have been known as antiviral agents efficacious against retroviruses such as AIDS virus (HIV) ("Shonika Shinryo", Vol. 54(4), pp. 981-987 (1991)). However, these agents delay the development of AIDS, but cannot accelerate healing and have severe side effects such as myelopathy.
In recent years, patients with immunodeficiency diseases induced by organ transplantation, cancer chemotherapy and HIV infections have been increasing, posing a grave medical problem. Virus infections in such patients are so diverse in type that they cannot often be treated with existing antiviral drugs. Thus, the development of more improved antiviral drugs and of more efficacious antiviral drugs for HIV and HCV is required.